Postpartum mood disorders (PMD) are the most common complication of childbirth and cause significant morbidity and mortality. Postpartum depression (PPD) has a prevalence of 10-15% and is the most frequent type of PMD. Postpartum psychosis (PP) is a rare but severe form of PMD that can result in tragic consequences including suicide and infanticide. The relationship between PPD and PP is uncertain, as is their relationship to major depressive disorder (MDD) and bipolar disorder (BIP). PPD may or may not be a variant of MDD, and PP may or may not be a variant of BIP. We propose here a rigorous investigation of the epidemiology and genetic epidemiology of PPD and PP using Danish national population registers. Moreover, in contrast to BIP or schizophrenia, efforts to identify the genetic basis of MDD have been complicated by etiological heterogeneity, and genetic studies of PPD may advance these efforts, as PPD may be a more homogenous phenotype involving exposure to a similar biopsychosocial stressor. A robustly replicable finding in psychiatric genomics has been risk profile scores (RPS-polygene scores). There is now strong evidence that RPS measure genetic liability to a psychiatric disorder. We propose to add RPS to our evaluation of the epidemiology and genetic epidemiology of PPD and PP as a critical mechanistic element. The Danish registers form the basis of a longitudinal study of nearly all health care contacts since 1968 and include 4.5 million women plus data on their partners, family members, and offspring. Moreover, at no cost to this study, we will be able to use individual genotypes from a large cohort. We propose: (1) to conduct a cohort study of risk factors of PPD and PP in Danish national registers to examine pre-pregnancy, pregnancy/puerperal and postnatal risk factors, (2) assess the genetic epidemiology using the Danish registers to aggregate the populace into pedigrees and estimate a) familiarity of PPD and PP, b) familial coaggregation of PPD with PP, MDD and BIP in first-degree relatives as well as for PP with PPD, MDD, and BIP, and c) estimate heritability and environmentality (shared and individual-specific) of PPD and PP; and (3) perform a mechanistic assessment of PPD and PP using RPS to develop a predictive model of who will develop PPD and PP and longitudinal risk of recurrent MDD and BIP. PMD are a first rank public health problem. We currently have a poor understanding of who will develop PPD or PP, and whether and how the two disorders are related. We urgently need improved understanding of the epidemiology, genetic epidemiology, and mechanisms of PPD and PP. These unique Danish population data provide the necessary sample sizes and statistical power for comprehensive longitudinal studies relevant to the mechanisms underlying PMD. Successful completion of this proposal would provide new knowledge crucial to understanding the risk factors and course of PMD that could eventually also prove to be key to understanding the etiology of mood disorders outside the perinatal period.